1. Field of the Invention
The current invention concerns generally a method for targeted delivery of local anesthetics for treatment of cough and tussive attacks and episodes. In one aspect, the invention concerns an improved anti-tussive solution for targeted delivery of a local anesthetic to lungs by nebulization. In particular, the invention concerns an improved anti-tussive lidocaine solution for targeted delivery of lidocaine into conducting and central airways as well as a method using said lidocaine solution for treatment of cough and tussive attacks or episodes.
The solution for inhalation comprising lidocaine or another local anesthetic is administered in daily dose from about 10 mg to 160 mg. Lidocaine or another anesthetic dissolved in a normal or diluted saline is nebulized into an aerosol having a mass median aerodynamic diameter (MMAD) within a range of 3 μm to 10 μm using an electronic nebulizer able to generate a substantially monodisperse particle spectrum. The solution comprising lidocaine or any other anesthetic nebulized according to the invention described herein is deposited predominantly in the target area for cough receptors, namely in the upper, conducting, and central airways, without any substantial residue of the anesthetic found in the oropharyngeal area or in the lower lungs.
In alternative, the local anesthetic solution suitable for treatment of cough may be administered nasally, orally or intravenously when appropriately formulated for such use.
For nasal administration, the local anesthetic is formulated as drops comprising about 2.5 mg of the drug in 0.3 ml of solvent. For oral administration, 50-100 mg of the drug is administered orally once or twice daily. For intravenous administration, the daily dose is up to 2000 mg administered once or several times a day.
The method for treatment of cough, asthma and tussive asthmatic attack is safer than the treatments described previously in that the secondary undesirable symptoms such as bronchospasm, loss of gag reflex and numbing of a pharyngeal region due to anesthetic properties of lidocaine or another anesthetic compound are prevented. The method is also more efficacious because it permits use of a lesser amount of lidocaine when the solution is nebulized using electronic nebulizer and delivers this solution in shorter time. Additionally, the electronic nebulizers produce a substantially monodisperse spectrum of particles substantially within a range of 3 μm to 10 μm of which a large percentage is deposited in the central airways.
2. Background and Related Disclosures
Cough is a natural response to mechanical and chemical irritation of trachea and bronchi. The physiological role of cough is to prevent aspiration of foreign objects or excess secretion within the respiratory tract and to remove such objects or secretion or exudates from the trachea and bronchi.
Cough is a very common problem in medical practice as it accompanies a great variety of viral or bacterial infections including pneumonia, cold or flu, or underlying diseases, such as asthma, emphysema, lung cancers, etc.
While there are several anti-tussive agents available on the market, most of these agents cause secondary undesirable symptoms, such as drowsiness, tiredness and some of these agents, such as for example codeine, are also addictive.
It would therefore be advantageous to have available a method for controlling cough which would have no such undesirable secondary symptoms.
In recent years, use of lidocaine was proposed as a supplemental treatment for suppression of cough and as pretreatment in instances where respiratory examination such bronchoscopy or X-rays could be affected by a patient's cough.
U.S. Pat. No. 6,362,197B1, for example, describes compositions possessing anti-tussive activity administered by nebulization using an ultrasonic, meter-dose inhaler, jet nebulizer and dry powder inhaler. As a pretreatment of testing a new anti-tussive quaternary ammonium compound in guinea pigs exposed to citric acid or capsaicin, lidocaine aerosol was generated using the UltraVilbis ultrasonic nebulizer (0.15 ml/min) and administered in dosages 0.1, 1, and 10 mg/ml. This pretreatment was shown to postpone a first cough at concentrations of 0.1 and 10 mg/ml, but not at 1 mg/ml and to significantly decrease a number of coughs at 10 mg/ml concentration.
JAOA, 98 (No 3): 170-172 (1998) describes the treatment of a patient suffering from a persistent refractory tussive syncope. The patient was unsuccessfully treated with a large number of anti-tussive drugs. Consequently, and in conjunction with these other drugs, the patient was treated with 1 ml of 1% nebulized lidocaine every 4 hours for 10 days. Such combination treatment of lidocaine with other anti-tussive drugs administered by nebulization or intravenously was able to resolve syncopal episodes.
Chest, 105:1592-93 (1994) describes treatment of chronic refractory cough with acetaminophen and codeine supplemented with 3 ml of 1% nebulized lidocaine twice a day for 6-10 weeks. The combination of nebulized lidocaine with other drugs was effective for treatment of refractory cough.
JAMA, 252 (No 17) 2456-2457 (1984) describes extended suppression of cough with inhaled 10 ml of 4% (40 mg) lidocaine administered by DeVilbiss nebulizer at a flow rate of 6 L/min for approximately 30 minutes. Under these conditions, after the first treatment cough was suppressed for about 9 weeks and for 7.5 weeks after the second administration. However, during this regimen, a substantial anesthesia of oropharynx was observed.
J. Canadian Assoc. Radiol., 22: 199-200 (1971) reference generically describes the use of local anesthetics as a pretreatment for bronchography. Local anesthetics are administered to the tip of the tongue prior to the procedure at a maximum effective concentration, determined for lidocaine to be 4%.
Am. J. Emerg. Med., 19:206-207 (2001) discloses lidocaine inhalation for cough suppression preceded by inhalation of nebulized albuterol. The lidocaine (1 ml of 1%) solution was diluted in 4 ml of saline to give 0.25% solution with oxygen 4-6 L/min delivered until nebulization was complete. Subsequently, 2 ml of the 1% solution was administered every 4-6 hours. Nebulization was preceded by delivery of 1 ml of albuterol and could be repeated every 4-6 hours, with even more concentrated solution (up to 4%). The reference further discloses that administration of lidocaine triggers bronchospasm requiring, as a pretreatment, administration of 5 mg of nebulized albuterol and/or 0.5 mg of budesonide. The doses of lidocaine were 10 to 20 mg every 4-6 hours up to 40-120 mg per day. Under these conditions, inhalation of lidocaine abolished cough but not bronchoconstriction.
Regional Anesthetics, 18:312-314 (1993) describes a treatment of persistent cough after stellate ganglion block. Treatment was achieved with nebulized lidocaine (1 ml of 2%) in 2 ml of normal saline solution administered at the same time as the oxygen mask.
British J. Pharmacol., 138:407-416 (2003) describes a novel antitussive agent, RSD931, and compared its activity to that of nebulized lidocaine in guinea pigs. The drugs were nebulized using an ultrasonic DeVilbis Ultraneb 2000 nebulizer and administered in amounts from 0.1 to 10 mg/ml. Lidocaine pretreatment had no significant effect on the time course of cough responses when administered as aerosol solution in these concentrations but did appear to delay onset of the first cough and reduce the total number of coughs. When used in from 10 to 30 mg/ml concentration, lidocaine pretreatment reduced the total number of coughs induced by capsaicin.
J. Appl. Physiol., 74: 1419-1424 (1993) describes the effect of nebulized lidocaine on ventilatory response to CO2 in healthy subjects. In this study, 10 ml of 4% lidocaine was nebulized with a Pulmosonic ultrasonic nebulizer or with a Wright jet nebulizer for 20 minutes. Particle size distribution and nebulizer output were determined. For Pulmosonic nebulizer, MMAD for lidocaine was 5.28 μm at nebulizer output of 0.16 g/min whereas for Wright nebulizer the MMAD for lidocaine was 1.76 at 0.25 g/min. This reference clearly shows that the ventilatory response to CO2 changes when administered by different nebulizers.
Am. Rev. Respir. Dis., 122:823-828 (1980) described effect of inhaled lidocaine on the ventilatory and airway responses using 4% lidocaine aerosol in patients with bronchial asthma. Lidocaine solution was aerosolized using a Vaponephrine nebulizer at a flow rate 5 L/min. Particle size was 5.6 μm, with time delivery between 10 and 15 minutes.
Br. J. Anaest., 54:853-856 (1982) describes the use of lignocaine for suppression of coughing. Lignocaine was administered (2 ml of 2%) before fibreoptic bronchoscopy. The reference discloses that when nebulized lignocaine is used as an antitussive agent before fibreoptic bronchoscopy, it suppresses cough within 10-15 minutes.
Thorax, 49:1166-1168 (1994) describes the use of nebulized lignocaine alone or in combination with adrenaline for suppression of capsaicin-induced cough. Lignocaine (20 mg) or a mixture of lignocaine with adrenaline (20 mg and 400 μm) significantly reduced coughing.
Br. J. Dis. Chest, 71:19-24 (1977) describes the use of lignocaine aerosol for treatment of intractable cough. Lignocaine (4 ml of 10%, i.e. 400 mg) was administered using a Monaghan nebulizer delivering particles between 5 and 20 μm. Inhalation took 15-20 minutes. Inhalation was repeated in intervals dictated by patient's response, in some patients every 6 weeks in others every four weeks or three weeks. Repeated inhalation was continued for half a year. The reference discloses that when nebulized lignocaine is used as an antitussive before fiberoptic bronchoscopy it suppresses cough within 10-15 minutes. However, the used nebulizer generates very large particle sizes requiring the ten times higher dose of the drug.
Europ. J. Anaest., 14:616-622 (1997) describes the advantages of alkalinized lignocaine for determination of tolerance of intratracheal tube and suppression of coughing during emergence from anesthesia. Lignocaine (3 ml 4%) or alkalinized lignocaine (3 ml 4%) are administered into the trachea.
All publications described above have certain shortcomings in terms of safety, time constrains, amount of lidocaine and tolerability for inhaled lidocaine or another anesthetic. Undesirable secondary symptoms associated with the administration of lidocaine are oropharyngeal numbing with loss of gag reflex, risk of aspiration of fluids and food, moderate to severe bronchospasm, and taste problems. In addition, none of the previous treatments are short in time and efficient enough to provide rapid administration and relief from cough.
From the brief description above, it is clear that there is a continuous need for an effective and improved therapy for treatment of acute and chronic cough or tussive attacks and episodes with novel compositions and devices. Such therapy would preferably comprise an inhalation of the aerosolized anesthetic formulation delivering a therapeutically effective amount of the drug directly to the endobronchial space of airways in a shortest possible time.
It is, therefore, a primary object of this invention to provide a method for treatment of cough and/or tussive attacks and episodes by providing a safe, physiologically acceptable and efficacious formulation for inhalation using a pure, preservative free solution or dry powder comprising lidocaine or another anesthetic compound, which formulation contains a sufficient but not excessive concentration of the active drug, which solution can be efficiently aerosolized by nebulization using an electronic nebulizer into an aerosol having a MMAD substantially within a range from 3 μm to 10 μm and a substantially monodisperse particle size spectrum, or a dry powder formulation having similar aerosol properties administered by a dry powder or metered dose inhaler. Both the nebulized solution and the dry powder are well tolerated by patients.
All patents, patent applications and publications cited herein are hereby incorporated by reference.